Hearing loss is a heterogeneous disorder that affects over 14 million people in the United States, with approximately 1 of every 1000 infants being affected by congenital deafness. An estimated one-half of congenital hearing loss cases are due to genetic causes (Bieber and Nance (1979) Clinical Genetics-A Sourcebook for Physicians, Jackson and Schimke, eds., Wiley, NY, vol. 60, pp. 443–461). More than 175 different forms of hereditary deafness have been characterized, including autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms (McKusick (1994) Mendelian Inheritance in Man, John Hopkins Univ. Press, Baltimore, Md.).
Genetic heterogeneity in hearing disorders both associated with other clinical anomalies (syndromic) and occurring as an isolated finding (nonsyndromic) indicates the involvement of a large number of genes in the complex development and function of the hearing process. Of the several hundred syndromic hearing loss disorders described (Gorlin et al. (1995) Hereditary Hearing Loss and Its Syndromes, Oxford Univ. Press, New York, N.Y.), only about 60 have been mapped to human chromosomes, with approximately half of these with characterized gene defects (Duyk et al., Nature Genet. 2:5–8, 1992; Petit, Nature Genet. 14:385–391, 1996). The majority of congenital hearing disorders are nonsyndromic (Cohen and Gorlin (1995) Hereditary Hearing Loss and its Syndromes, Gorlin, Toriello and Cohen, eds., Oxford Univ. Press, New York, N.Y., vol. 60, pp. 9–21), but even fewer nonsyndromic disorders have been identified. This number is increasing through the study of consanguineous geographically isolated families. Over 40 human chromosomal loci associated with nonsyndromic hearing impairment have been identified, some with corresponding mouse mutants in the homologous region (Petit (1996), supra; Van Camp et al., Am. J. Hum. Genet. 60:758–764, 1997). However, to date, only a small number of nuclear genes responsible for nonsyndromic hearing impairment have been discovered: POU3F4 in DFN3 (de Kok et al. Science 267:685–688, 1995); MYO7A in DFNB2 (Liu et al., Nature Genet. 16:188–190, 1997; Weil et al. Nature Genet. 16:191–193, 1997) and DFN11 (Liu et al., Nature Genet. 17:268, 1997); POU4F3 in DFNA15 (Vahava et al., Science 279:1950, 1998); PDS in DFNB4 (Li et al., Nature Genet. 18:215, 1998); TECTA in both DFNA8 and DFNA11 (Verhoeven et al., Nature Genet. 19:60, 1998); and GJB2 in DFNB1 and DFNA3 (Kelsell et al., Nature 387:80–83, 1997).
Thus a need still exists to identify novel human genes responsible for hearing defects.